Another actress died of cancer, but is it useful even when it comes to genetic testing?

Lei Feng Network Press: This article released by Deeperblue Lei Feng network.

At 4 pm on September 7, 2016, actress Xu Ting died of acute lymphoma and lung infection at the Beijing 304 Hospital. He was only 26 years old. Although not a big star, the girl's life experience and illness have become the focus of the day.

“There is still a long way to go for humans to use genes to describe the journey of cancer.” — Jessica Wapner, “The Philadelphia chromosome: An exploration of genetic mutations and the treatment of cancer at the gene level.”

On July 16, 2016, Zhang Hua (a pseudonym) father died of lung cancer. From examining lung cancer to death, it took only 9 weeks. This is a huge psychological blow to Zhang Hua. After the death of his father, in addition to grief, Zhang Hua's reaction was to do a systemic cancer genetic test for himself. She heard people say that family members of the immediate family who have cancer have an extremely high chance of "inheriting" cancer.

“Just spend some money to be assured.” Zhang Hua told Deep Blue Blue . “In addition to my dad, my immediate family members, grandfather and aunt, also had cancer. Now I am married and I’m going to have children. I don’t want my kids to For the mother who died young."

Due to the impact of cost differentials and agency profits of various agencies, the price difference between genetic testing for cancer across the entire group is very large. In China, the maximum price for whole-genome testing can reach 67,000 to 70,000, and low-time, 15,000 can also be done.

"I was inquiring at the time about a testing institute in Wuhan. My friend recommended that it tell me that I am the largest genetic laboratory in Asia and can do whole group gene sequencing for healthy people, about 50,000 or 60,000." Zhang Hua said, "Someone also suggested I went to the United States to do whole genes for healthy people and charge hundreds of thousands to hundreds of thousands."

In February 2013, Angelina Jolie decided to remove the breast mammary glands. Julie's mother has had ovarian cancer for nearly 10 years. At the age of 56 she sustained her first grandson and died. As a mother of six children, Julie went to test her own genes. The test report shows that she carries the cancer susceptibility gene BRCA1 (Breast Cancer Susceptibility Gene 1), a gene closely related to breast cancer. The doctor told her that the chance of getting breast cancer is about 87%, and the risk of ovarian cancer is 50%.

"After surgery, my chance of developing breast cancer has dropped from 87% to 5%," said Julie in a letter to The New York Times. "Now, I can tell the children that mothers will not suffer from breast cancer. And died.” Just two years later, in March 2015, Julie removed the ovaries.

Thanks to Angelina Jolie, cancer genetic testing has become public. Now, more and more women choose to remove the breasts and ovaries before getting cancer.

The number of women who chose to do BRCA tests after Angelina Jolie wrote the open letter "My Medical Choice" increased by 40%.

In January 2016, President Obama announced in his State of the Union address a “National Cancer Landing Plan” directly led by Vice President Biden, funding a total of one billion U.S. dollars for related cancer research, and using the 60’s moon landing plan to imply “ Humans will eventually overcome cancer." The plan will coordinate more than a dozen organizations, including the US Department of Defense, the U.S. Food and Drug Administration, the National Institutes of Health, and the National Science Foundation, in an effort to double the pace of conquering cancer in five years.

However, "this task is arduous and complex. At present, human knowledge of genes is not enough to bring real benefits to cancer patients. " Jessica Wapner's nine in Scientific American 2016 The monthly wrote. Previously, she wrote the book "Philadelphia chromosomes: genetic mutations and exploration of gene therapy to treat cancer."

“We are still in a transitional stage,” said Stephen Chanock, director of the Cancer Research Center for Cancer Epidemiology and Genetics at the American Cancer Research Center.

Cancer genetic testing began in 1995 and scientists have established a correlation between genes and cancer. But the problem is far from simple. How useful is cancer gene sequencing in the end?

There are not a few people who have cancer genetic tests like Zhang Hua because of panic. “My immediate family members have a history of cancer” as a reason to “have to undergo cancer genetic testing”.

In the United States, the share price of the famous genetic testing company, Illumina, has increased six-fold in the past four years, and the current market value has reached US$27 billion. Some domestic start-up genetic testing companies have publicly reported in the media that the annual conference will present their employees with BMW cars. It is people's fear of cancer that nourish this market.

Illumina official website

Cancer is a general term for a wide range of diseases, and what they have in common is the loss of controlled cell proliferation. Under normal conditions, the cells in our body grow, divide and die at a normal rate, but the growth rate of cancer cells is crazy. This immortal cell loses control and the human body eventually dies because it cannot tolerate it.

Uncontrolled cancer cells can grow crazy indeed because of genetic variation. However: Can cancer be inherited?

If it is, Lai reincarnation. If not, Lai himself.

There are two types of genetic mutations that can cause cancer: the first is heritable, occurs in germ cells, and is primarily inherited from parents. The second type of mutation is not related to heredity. It occurs in somatic cells and is mainly caused by age, smoking or other environmental factors. For example, sun exposure can cause skin cancer; HPV virus can cause cervical cancer; smoking can cause lung cancer.

Although heritable mutations in DNA can lead to some malignancies, including some childhood cancers, these mutations are relatively rare. The vast majority of human cancers are caused by somatic mutations that have nothing to do with geneticity - according to the American Cancer Society, only about 5% to 10% of cancers are genetic.

Researchers at the University of Washington Medical School analyzed the relationship between 12 cancers and heredity by analyzing reproductive gene information from more than 4,000 cancer cases. The results are shown in the following table:

The results of this study were published in Nature's subsidiary Nature Communications, December 2015 issue.

The results showed that the most genetically related cancer was ovarian cancer, with approximately 19% of patients carrying germline mutations, and only 4% of patients with acute myeloid leukemia carried this mutation. In other words, even the most relevant type of cancer is only 19% genetically related.

Even if her husband had passed away, unlike Zhang Hua, Zhang Hua’s mother completely did not believe in cancer genetic testing. Although her daughter repeatedly “forced” her to do tests with herself, she still refused.

“This thing is not down to earth.” Zhang Hua’s mother told Deep Blue Blue . “Not as good as the health check provided by the top-three hospitals. I know that 23andMe in the United States, spit on water, and be a cancer test, just like the game.” This kind of testing is not rigorous or scientific, and it costs 99 dollars to know the little secret on the body. It is not authoritative."

Zhang Hua’s mother’s assessment is not unreasonable. Because there is no uniform standard for gene detection, companies choose their own instruments, sequencing sites, assessment methods, and databases. Even if they are the same, the test results are not the same.

“Now patients often carry various so-called gene detection reports to hospitals and claim that they have a high risk of cancer and are treated by doctors. However, after inspection, they found that there were no solid tumors and even no precancerous lesions.” Guangdong Provincial People's Hospital Deputy Director Zhong Wenzhao said in an interview that the technology for predicting cancer is not mature.

The cancer test report issued by 23andMe caused public panic and even overtreatment. Large numbers of women chose to have their ovaries removed because they received a "risk warning report." In fact, there is no scientific basis for this. In 2013, the FDA stopped 23andMe's disease-related genetic testing services.

In the past, users only needed to spit saliva into the collection tube and spend 99 dollars to know that they were suffering from more than 240 diseases such as diabetes, heart disease and breast cancer.

"Why even after spending this money, knowing that I have susceptibility genes, what can I do? Cut off the ovaries and the like. Maybe. But if there is a problem in the digestive tract... Can I digest the digestive tract?" Zhang Hua The mother said, "If I have a lot of money, I will try to do it, but I have no money. I would rather spend this money to buy something delicious."

In fact, even if cancer has been diagnosed, the correlation between cancer and genetic mutations has so far not been scientifically rigorously systematically certified.

As mentioned above, the essence of cancer is the uncontrolled reproduction of cells. The vast majority of human cancers are caused by somatic mutations.

Most somatic mutations are harmless, and many of them are repaired by the body's own quality-control processes. However, there are always some somatic mutations that can cause confusion and uncontrolled proliferation.

In the case of cell carcinogenesis, harmful gene mutations do two things: they encode special proteins and actively promote the cells to over-replicate; stop the cell's own "brakes" function and lose control of replication.

Scientists who cause cancer, genetic mutations referred to as driving the development of gene mutations (driver mutations); and some meaningless, does not directly cause cancer, called "passenger mutations", that is the non-driving mutations (passenger mutations ). It is well understood that in the event of a car accident, the vast majority of cases are driver's pots and have nothing to do with passengers.

Drive mutations are meaningful for diagnosis and treatment of cancer. The often-tested detection of cancer molecular markers is in many cases the detection of driver mutations. For example, in the diagnosis of lung cancer, the doctor tests the expression and expression level of certain mRNA (general tissue) or DNA (blood) in vivo, and assesses whether the relevant driver mutations (such as KRAS mutations and EGFR mutations that cause lung cancer) exist.

But the problem is that although we know that drive mutations are found in cancer, we don't know which mutations drive the genes that cause cancer, nor do we know to what extent drive mutations can cause cancer.

"There are two kinds of cancer gene mutations. One is like EGFR mutations in lung cancer. You know where mutations cause certain functional defects in the corresponding proteins, and drugs that target these functional defects usually Cancer treatment helps a lot." Sarah Yang told Deep Blue Blue that she had a Ph.D. in biology from Stanford University.

"There is another category of mutations that are confirmed by the correlation between genome sequencing and the incidence of cancer. This is a statistically relevant correlation, such as the KRAS mutation. The current science does not know the pathogenic principle of specific KRAS mutations at all. In fact, KRAS has a high correlation with many types of cancer. This type of medicine is actually not very helpful in guiding the treatment of cancer."

Relevance and causality are two very different logical concepts that are easily confused. Even if it is statistically proven that certain driver mutations are associated with the disease, they do not prove that these mutations necessarily lead to the onset of cancer.

In addition, no one knows how many driver mutations will induce cancer. On average, two to eight driver mutations can induce cancer, and another study published in the 2006 Science Journal found that in some colon and breast cancers, as many as 20 driver mutations can be induced Cancer.

Zhang Hua’s father had done whole-genome testing and related drive gene testing before his death.

From the genetic test reports he got, Zhang Hua obtained the most effective information: where did the father's body mutate, and did these mutations have any corresponding drugs to treat?

“But even the genetic laboratory known as 'the largest in Asia' does not work closely with pharmaceutical companies and clinical institutions. After we got this report, we were still very confused. My dad’s medicine, finally found It is said that in clinical trials, the failure rate is as high as 80%... What is the use of this?” said Zhang Hua.

the reality is cruel. Even if a clear genetic mutation was found, there are only 104 targeted drugs for cancer, of which only 25.4% are listed in China. The genetic detection distance really plays a role in the clinic and helps cancer patients. There is still a long way to go.

The movie "Dallas Selling Club" chronicles the story of 1986 AIDS patient Ron Woodroof trying to self-rescue and researching all kinds of drugs that are not approved by the authorities and deploying combination drugs by himself to smuggle drugs to other patients. . In real life, cancer patients and their families are also struggling on this line of life and death.

The stories in the movie are staged every day in India. Targeted drugs that are not listed in the country and low-priced generic drugs are transferred from India.

Chiu Weini, the founder of cancer big data company Haalthy, has seen too many "Ron Woodruff." When she was still studying at MIT in 2012, she was asked by various people to look for raw materials at the Patent Office and bring her back to her own lifesaving medicine.

When Zhang Hua was most desperate, she had grasped a glimmer of hope to get through the parties to know Qiu Weini, and wanted her father to be able to make an extra living. But she did not have the good fortune of Qiu Wei Ni – like Zhang Hua’s father, Qiu Weini’s father also suffered from lung cancer, but he had the privilege of entering a clinical trial group in Hong Kong. Although, three years later, Qiu Wei Ni's father did not survive.

Just like the unrescued lifeboat at the time of the sinking of the cruise ship, genetic testing took the patient from the shipwreck, but the patient still faced the threat of freezing on the surface of the sea.

Many patients still find that they have no medicine to cure after they have done genetic tests. For example, 90% of patients with pancreatic cancer have KRAS mutations, but so far people have not found drugs that can deal with mutations in cancer cells.

It is not easy to produce drugs that can suppress mutations. Some abnormal proteins encoded by somatic mutations are located on the surface of cancer cells, facilitating the arrival and onset of drugs. However, many of them are buried deep in cells, so that even if drugs can cross the cell membrane and reach the target protein, they are often too small to bind to these proteins and have an effect. This problem has caused some of the most common driver mutations to be unresolved - such as P53 and RAS mutations. These two mutations can cause normal cells to become cancerous cells uncontrolled.

Even if some drugs can successfully suppress mutations, their life extension for patients is still minimal. For example, there is a drug that successfully suppresses a driver mutation and shrinks the tumor, but as soon as a drug-resistant cell survives, the cell can proliferate into a new tumor and it will not respond to the drug.

For example, Gleevec, a drug used to treat gastrointestinal stromal tumors, can increase the median survival of patients with advanced cancer from 19 months to 60 months, but 60% of patients will develop drug resistance within two years.

In the future, cancer, like AIDS, may need to be treated with a combination of drug-based cocktails, such as combination therapy for advanced colon cancer. However, each of these drugs is costly and has its own side effects.

" The significance of cancer genetic testing is still medication-based. There are family history and a lot of money, you can play." Justin Zhang told Deep Blue , Deep Blue , he is an in vitro diagnostic investor, "definitively diagnosed, done There is no medicine, but no hope is lost. There are medicines that depend on the situation. Many patients are drug-resistant soon after the drug is used, or they have no bottom holes."

For breast cancer patients, doctors need to develop treatment plans based on the results of the test of genetic tests, and there are currently no effective drugs for patients with certain mutations.

To date, no one has ever dared to say that cancer gene test results can be perfectly interpreted.

Struggling clinical doctors can only find mutations in which driver genes of patients, but they do not know what these mutations mean. Unless we can record all possible driver mutations in the patient and observe the patient's clinical data at the same time. However, this record itself is extremely difficult.

The horror of cancer cells lies in the abundance of mutations.

The number of mutations in tumors of cancer patients is not the same. There are less than one thousand children's cancers. There are more than 100,000 lung cancers and melanomas caused by smoking. Finding no more than 20 driver mutations in so many mutations is no different from a needle in a haystack.

In the process of tumor growth, new mutations always occur. In addition to exploring which gene mutations cause cancer, researchers have to find out which genes will promote the further development of cancerous tissues. The occurrence of mutations in each wave of genes will cause the classification of driver mutations and passenger mutations to be disrupted. Patients will develop resistance to previous drugs and doctors will have to reformulate treatment plans.

If you want to establish the relationship between genes and diseases, you need to constantly test the patient's genes to understand the dynamic changes in the genome.

In order to solve these difficulties, scientists need to collect and analyze data.

To this end, two related cancer gene big data projects have been initiated internationally: the Cancer Genome Atlas (TCGA) and the International Cancer Gene Consortium (ICGC).

After 10 years of cancer genomic mapping, it has established the world's largest database of cancer gene information, collecting 220 million PB of genetic data and discovering nearly 10 million cancer-related mutations. Using this database, scientists can either start with a gene, search for the type of mutation found in the gene, how it is found, and the frequency of occurrence in the tumor, respectively, or start with a cancer and search for all affected genes.

The International Cancer Gene Consortium (ICGC) is composed of 71 research institutions from around the world. It aims to perform genome-wide detection and analysis of more than 50 types of cancer worldwide, and to open up all test results for doctors and scientific researchers. Convenient, free usage of data. Currently, ICGC has 13 cancer-related gene sequencing including lung cancer, gastric cancer, liver cancer, and breast cancer in China.

The ICGC announced the most common 20 cancer-related mutations in the world and in China.

This is a war of big data. Humans are still struggling.

Of course, cancer gene sequencing is not used for anything...

For example, cancer genetic tests help patients with melanoma. About half of the melanoma patients have mutations in the BRAF gene. This is called BRAF gene, the main harm is to help cancer transfer to other parts of the body. In 2011, the FDA approved the first drug that can inhibit the BRAF mutein. Until 2016, the average survival time of 80 patients with metastatic melanoma who received new therapy reached two years, which was far longer than the previous 5.3 months.

"There is a systemic disease in the tumor. It's not a gene that has a problem. It's a problem with a bunch of genes. The tumor is refractory because it's a problem of multiple genes, and it's far more complicated than simple gene sequencing. The role of immunotherapy can't be underestimated. Even if there is no targeted drug, the efficiency of immunotherapy can still be estimated.” Qia Weini, the founder of Haalthy, told Deep Blue .

More importantly, gene sequencing can help determine resistance mechanisms. For example, EGFR mutations and ALK mutations found in lung cancer, if resistance occurs, can be used in 50% of patients if genetic sequencing is performed.

"Driver gene tests are worth trying, such as some of the associated mutations in lung cancer, and as long as physical conditions permit, targeted drugs can be used immediately according to the National Comprehensive Cancer Network (NCCN) guidelines." Qiu Wei Ni said, "Genetic tests can not solve all tumors Problem, but it is the basic thing."

At least, genetic testing has made people have a new understanding of the classification of cancer.

In the past, the classification of cancer was based on the location of the first cancer cells: breast cancer, lung cancer, etc. But later it was discovered that gene mutations in tumors are more essential things. As a result, the medical profession has slowly begun to combine the site of tumor development with its genetic information to classify and name cancer. This shift in perception opens up new ideas for cancer treatment.

After genetic testing, doctors will develop treatment plans based on genetic testing information. For example, in the same lung cancer, patients with EGFR mutations can take targeted drugs such as Iressa, Tarceva, afatinib, and 9291, and if there is an ALK mutation, they need to choose crizotinib and ceramide. Treatment with nigra, alatinib, etc.

In simple terms, as long as the mutations in the two tumors are the same, their treatment is the same. For example, breast cancer and colon cancer have no relation at all. However, when the Herceptin, a breast cancer drug used to treat the HER2 mutation, is used in patients with advanced colon cancer with the same mutation, approximately half of the patients survive. For more than one year.

Scientists are using genetic mutations to explain the long journey on the journey of cancer. But now, they are still surrounded by questions: How long does it take for genetic testing to bring meaningful changes to cancer treatment?

At least for now, this road is still far away.

references

Jessica Wapner, Scientific American, September 2016 Issue, http://?from=singlemessage&isappinstalled=0

Spigel, DR, AB Schrock, and D. Fabrizio. "Total alteration burden (TMB) in lung cancer (LC) and relationship with response to PD-1/PD-L1 targeted therapies." J. Clin. Oncol. 34.May (15_Suppl.) (2016): 9017.

Schwartzberg, Lee S. "Post-ASCO Immunotherapy Highlights (Part 2): Biomarkers for Immunotherapy." (2016).

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